The present invention is directed to a process for preparing alpha,alpha-difluoroketones from alpha,alpha-difluoroacylsilanes and diazo compounds via an intermediate enolic silyl ether derivative, i.e., EQU (II)+(III).fwdarw.(IV).fwdarw.(I)
according to the formulas depicted below.
The incorporation of fluorine into organic molecules frequently effects profound changes in the biological profile of the fluorine substituted compound in comparison to the unsubstituted compound. Such changes result from the extreme electronegativity of fluorine, as well as its ability to replace hydrogen without significant steric consequences. New methods for the introduction of fluorine are thus of great interest. It follows that the alpha,alpha-difluoroketones which result from the present process are of special value as intermediates in the preparation of various medicinal agents; for example, compounds which inhibit phospholipase A.sub.2. This enzyme catalyzes the liberation of arachidonic acid from the phospholipid membrane pool, the rate-determining step in the biosynthesis of prostaglandin, leukotrienes, thromboxanes and prostacyclin, compounds which play important roles in a variety of disease states; see, Gelb, J. Am. Chem. Soc., vol. 108, pp. 3146-3147 (1986), Yuan et al., ibid., vol. 109, pp. 8071-8081 (1987), and leading references there cited.
Certain alpha,alpha-difluoroketones have been previously prepared via the Claisen rearrangement of difluorovinyl ethers of allylic alcohols; Metcalf et al., Tetrahedron Letters, vol. 26, pp. 2861-2864 (1985). Many of the present alpha,alpha-difluoroacylsilane starting materials are prepared according to methods there disclosed.